Parathyroid hormone (hereinafter, PTH) is produced by the parathyroid gland and is involved in the control of calcium levels in blood. It is a hypercalcemic hormone, elevating blood calcium levels. PTH is a polypeptide and the amino acid sequences of bovine and human PTH are closely related. Only the residues at locations one, seven and sixteen differ between the two. Synthetic polypeptides containing the first thirty-four residues of PTH may be prepared using the method disclosed by Erickson and Merrifield, The Proteins, Neurath et al. , Eds., Academic Press, New York, 1976, page 257, preferably as modified by the method of Hodges et al., Peptide Research, 1, 19 (1988).
When serum calcium is reduced to below a "normal" level, the parathyroid gland releases PTH and resorption of bone calcium and increased absorption of calcium from the intestine, as well as renal reabsorption of calcium, occur.
The antagonist of PTH is calcitonin, which acts to reduce the level of circulating calcium. PTH is known to stimulate osteoclasts and its activity requires the presence of derivatives of vitamin D.sub.3, especially 1,25-dihydroxycholecalciferol.
Intracellular calcium, particularly in the cells of the vascular system, has been shown to affect changes in vascular tension, as can be measured by changes in blood pressure. U.S. patent application Ser. No. 603,745 describes one method which has been discovered to regulate calcium uptake in vascular cells.
Osteoporosis is a progressive disease which is particularly characteristic of postmenopausal women, and results in the reduction of total bone mass. The sequelae frequently involve fractures of load-bearing bones and the physical degenerations characteristic of immobilizing injuries. osteoporosis is associated with hyperthyroidism, hyperparathyroidism, Cushings syndrome and the use of certain steroidal drugs. Remedies historically have involved increase in dietary calcium, estrogen therapy and increased doses of vitamin D.
PTH has been used to treat osteoporosis. However, while the use of PTH is effective in the treatment of osteoporosis by diminishing the loss of bone mass, PTH may exhibit other undesired pharmalogical effects, such as hypotension and smooth muscle relaxation (e.g. relaxation of gastrointestinal organs, uterus, tracheal and vas deferens) as well as positive chronotropic and inotropic effects on the heart. The relaxation effects of PTH on smooth muscle as well as positive chronotropic and inotropic effects of PTH are described in Pang et al, Trends in Pharmacological Sciences, Vol. 7, No. 9, pp. 340-341 (September 1986).
U.S. Pat. No. 4,771,124 discloses the property of bovine and human PTH analogues wherein Trp.sup.23 is substituted by amino acids phenylalanine, leucine, norleucine, valine, tyrosine, beta-naphtylalanine and alpha-naphtylalanine as a PTH antagonist. While it was suggested that these analogues might be useful in the treatment of osteoporosis, it was based on the analogues antagonistic action to PTH. Furthermore, there was no data to indicate the effectiveness these analogues on bone or other tissue. In addition, analogues with substituted at Trp.sup.23 with leucine, phenylalanine or tyrosine would produce undesired secondary effects of smooth muscle relaxation, vascular smooth muscle calcium change as well as positive chronotropic and inotropic effects on the heart.
Because PTH is a peptide, topical administration would be the preferred method of administration. However, topical application of PTH or the aforementioned analogues which exhibit vasoactivity would likely produce an undesired local vascular reaction. This reaction could be potentially detrimental if, for example, nasal administration is employed.
It is one object of this invention to ameliorate bone loss while preventing smooth muscle relaxation as well as positive chronotropic and inotropic effects on the heart and without significantly changing blood pressure. It is another object of this invention to identify that portion of PTH which is responsible for calcium regulation and that portion which appears to be primarily related to control of blood pressure and smooth muscle action.